Lymphedema is a debilitating condition characterized by chronic tissue edema and impaired immunity. At present, no curative treatment is available for lymphedema patients, as current practice involves palliative care only. The principal cause of lymphedema in industrialized is surgery or radiation therapy of the armpit region to eradicate breast cancer metastases. Skin flap survival following surgical procedures, especially reconstructive surgical procedures, is often compromised by, among other complications, infection, ischemia and tissue edema. Tissue and skin flap breakdown remain a major problem in plastic surgery, especially in patients suffering from diabetic microangiopathy or other forms of peripheral vascular disease. In such patients wound healing is often delayed and defective and in these patients complications may lead to necrosis and eventually require costly and painful secondary surgical procedures.
The vascular endothelial growth factor (VEGF) family currently includes six members, which are important regulators of angiogenesis and lymphangiogenesis: VEGF, placenta growth factor (PlGF), VEGF-B, VEGF-C, VEGF-D, and VEGF-E. VEGF is also known as vascular permeability factor, and it is more potent than histamine in increasing capillary permeability to plasma proteins. VEGF binds selectively and with high affinity to receptor tyrosine kinases VEGFR-1 and VEGFR-2. Angiopoietins (Angs) constitute another family of endothelial growth factors that are ligands for the endothelium-specific receptor tyrosine kinase, Tie-2 (Tek). Although Angs do not appear to induce new vessel growth, they may be involved in vessel stabilization. Vascular permeability induced by VEGF, for example, is reported to be blocked by angiopoietin-1 (Ang-1).
The lymphatic vasculature transports fluid and macromolecules from tissues back to the blood circulation and links tissue fluids to lymph nodes as an immune surveillance system. Metastatic tumor cells frequently spread via the lymphatic vascular system and colonize lymph nodes. Breast cancer and melanoma in particular frequently spread to lymph nodes, necessitating radical surgery that destroys lymphatic vessel network and leads to impairment of afferent lymphatic flow. Approximately 20-30% of patients that have undergone radical axillary lymph node dissection develop lymphedema later on. Lymphedema is a progressive disease characterized by gross swelling of the affected limb, accompanied by fibrosis and susceptibility to infections.
Damage to the collecting lymphatic vessels causes the vast majority of all lymphedemas, and it has been estimated that several million patients suffer from such acquired lymphedema in the USA alone. In contrast, Milroy disease and other rare hereditary forms of lymphedema are caused by defects in lymphatic capillaries. Tyrosine kinase-inactivating point mutations of the VEGFR3 gene have been identified as a major cause of Milroy disease, and VEGF-C therapy has shown promising efficacy in preclinical animal models. However, previous work has only demonstrated lymphatic capillary reconstitution, whereas effects on the collecting lymphatic vessels that are more commonly damaged in lymphedema have not been addressed.
It has been reported that autologous lymph node transfer appears to have a favorable and persistent effect on postmastectomy lymphedema in humans. Lymph node transplantation may be used to treat limb lymphedema with other procurement sites such as cervical or auxiliary being possible.
Lymphatic vasculature plays a key role in the maintenance of tissue fluid homeostasis by collecting and draining extravasated fluid and macromolecules back to the blood circulation. The lymphatic system also has a major role in immune defence. Therefore, lymphatic vessels and lymph nodes are involved in several human diseases, such as lymphoedema, inflammation and tumour metastasis. The lymphatic capillaries in the peripheral tissues merge with larger collecting lymphatic vessels, specialized for the transport of large volumes of lymph, and connect with chains of lymph nodes. Chronic lymphoedema, caused commonly by infection and surgical or radiation therapy of metastatic cancer, remains a common clinical problem that lacks curative options. The effective treatment and staging of cancer often requires removal of regional lymph nodes and the associated collecting lymphatic vessels to eradicate metastases. This leads to a disruption in the lymphatic flow of the operated area, which frequently leads to lymphoedema of the affected limb. The conventional treatment for chronic lymphoedema aims at alleviating the symptoms and is mainly based on physiotherapy and/or controlled compression therapy, whereas surgical treatment options are limited. This is chiefly due to difficulties in identifying and preserving the lymphatic vessels even by modern microsurgical methods. Recently a microvascular lymph node transfer into axillas of patients that had undergone axillary lymph node dissection in response to disseminated breast cancer was shown to improve lymphatic drainage in some patients.
Understanding of the mechanism of lymphangiogenesis has increased considerably in recent years. Vascular endothelial growth factors (VEGFs) are important regulators of both angiogenesis and lymphangiogenesis. VEGFs stimulate cellular responses by binding to tyrosine kinase receptors (VEGFRs) that are specifically expressed in blood and lymphatic cells that line the luminal surface of vessels. VEGF-A binds to VEGF receptor-1 (VEGFR-1) and VEGFR-2 and induces mainly angiogenesis. VEGF-C and VEGF-D signalling via VEGFR-3 induce lymphangiogenesis. However, the proteolytically processed short forms of both VEGF-C and VEGF-D also bind to VEGFR-2, and have blood vascular effects in some tissues.
The treatment of lymphedema is currently based on physiotherapy, compression garments, and occasionally surgery.
US 2008-0267924 reports autologous lymph node transfer in combination with VEGF therapy, for the treatment of secondary lymphedema. The contents of US 2008-0267924 are hereby incorporated herein by reference.
US 2008-0267924 reports that intranodal administration of VEGF is preferred. All the relevant examples report intranodal administration. There is reference in the description to administration into “non-lymph node” tissue. However, this is not further defined.